CN103068388A - Combination of glyt1 compound with antipsychotics - Google Patents

Combination of glyt1 compound with antipsychotics Download PDF

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CN103068388A
CN103068388A CN2011800387771A CN201180038777A CN103068388A CN 103068388 A CN103068388 A CN 103068388A CN 2011800387771 A CN2011800387771 A CN 2011800387771A CN 201180038777 A CN201180038777 A CN 201180038777A CN 103068388 A CN103068388 A CN 103068388A
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fluoro
piperazine
mesyl
pyridine
ketone
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丹尼拉·阿尔贝拉蒂
让-吕克·莫罗
约瑟夫·G·韦特施泰因
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Abstract

The present invention relates to a pharmaceutical combination of a glycine transporter inhibitor (GlyT1) and an atypical antipsychotic drug which may be used for the treatment of positive and negative symptoms of schizophrenia.

Description

The combination of GLYT1 chemical compound and psychosis
The present invention relates to the drug regimen of a kind of glycine transporter inhibitors (GlyT1) and atypical antipsychotic agents, described drug regimen can be used for the treatment of the schizoid positive and negative symptoms.
Schizophrenia is a kind of serious chronic mental sickness, and its sickness rate is estimated in the scope of 1.4 to 4.6/1000 populations [2.1].Schizophrenic disturbance is united by the h and E factor and is caused that it is unusual that it is included in neurodevelopment possible in grey matter and the white matter structure.For the basis of symptomatic phenomenon, monoamine energy and Glutamatergic neurotransmission (for example, dopamine, 5-hydroxy tryptamine, epinephrine, norepinephrine, glutamine) imbalance have been proposed.
These approach extensively are present among the CNS, and therefore can affect potentially a plurality of zones that participate in consciousness, emotion processing, cognition and behavior.Up to date, the dopamine hypothesis is schizoid main pathology physiological theory, and this is based on the effectiveness of D2 antagonist in the acute exacerbation of this disease of control to a great extent.
Schizoid symptom typically occurs during teenager or early adulthood, usually divides positive, feminine gender or awareness.The positive symptom comprise hallucination, vain hope, suspicious, thought is mechanical (stereotyped thinking), human body anxiety (somatic concern), thundering content of thought or lack judged and insight.Negative symptoms is one group of defective, and it comprises that the blunting of affect, emotion shrink back (emotional withdrawal), concern that poor (poor rapport), passive/cold and detached social activity shrink back, lack the self awareness of talk and fluency, bradykinesia or social activity initiatively and avoid.The awareness defective also is the outstanding characteristic [2.2,2.3] of this disease such as working memory power, language memory, attention and execution function.
Present atypical antipsychotic agents is being effectively aspect the management positive symptom mainly, but is having minimum effect for negative symptoms and cognitive defect except relevant with significant side effect.The two effective treatment is the demand [2.3] that schizophrenia fails to satisfy most to positive and negative symptoms and cognitive defect, [2.4].
First generation antipsychotic drug is effective, but relevant with significant extrapyramidal symptoms sickness rate, and the second filial generation (atypia) psychosis has the less tendentiousness that causes EPS, but relevant with sickness rate and the seriousness of the rising of metabolism syndrome.
Being used for the treatment of schizoid common psychosis is olanzapine (2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2.3-b] [1.5] benzodiazepine
Figure BDA00002825167200021
).Olanzapine belongs to the medicament categories that is called atypical antipsychotic agents.Other members of this kind comprise Paliperidone (paliperidone) (3-[2-[4-(6-fluoro-1,2-benzisoxa
Figure BDA00002825167200022
Azoles-3-yl)-and piperidino] ethyl]-6,7,8,9-tetrahydrochysene-9-hydroxy-2-methyl-), risperidone (3-[2-[4-(6-fluoro-1,2-benzisoxa
Figure BDA00002825167200023
Azoles-3-yl) piperidino] ethyl]-2. methyl-6,7,8,9-tetrahydrochysene-4H-pyrido-[1.2-a] pyrimidin-4-one), Aripiprazole (aripiprazole) (7-{4-[4-(2,3-Dichlorobenzene base) piperazine-1-yl] butoxy-3,4-dihydroquinoline-2 (1H)-ketone), Quetiapine (quetiapine) (ethanol, 2-[2-(4-dibenzo [b, f] sulfur azepine
Figure BDA00002825167200024
(thiazepin)-and 11-base-1-piperazinyl) ethyoxyl]-) and Ziprasidone (ziprasidone) (5-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one).
Being used for the treatment of schizoid modal medicine is olanzapine.Olanzapine is bonded to α-1, dopamine, histamine, muscarine and 5-hydroxy tryptamine 2 types (5-HT2) receptor.
Olanzapine is approved for the long-term treatment of schizoid treatment, bipolar disorder and is used for the treatment of the paralepsy relevant with bipolar disorder and is used for the treatment of refractory depression with the fluoxetine combination.
Utilize the treatment of psychosis such as olanzapine can cause serious side effect.Food and FAD (The Food and Drug Administration) require all atypical antipsychotic agents to comprise that these two kinds of diseases are the factors in the metabolism syndrome about the warning of development hyperglycemia and diabetes risk.These effects may be relevant with the ability that drug-induced body weight increases.The rising blood sugar level of using other antipsychotic drug of olanzapine ex hoc genus anne to exist to increase and the risk of type ii diabetes.
Therefore, there is demand for the safety that has improvement with respect to present atypical antipsychotic and the new therapy of toleration characteristic.For example, new treatment should be with body weight increase, extrapyramidal sign or on the impact relevant [2.4,2.5,2.6] of glucose and lipid metabolism.
The objective of the invention is a kind ofly to comprise atypical antipsychotic agents and as the drug regimen of the chemical compound of the inhibitor of GlyT1, described drug regimen is used for the treatment of schizoid feminine gender and the positive symptom, and does not affect/increase the known side effect profile that is caused by independent atypical antipsychotic treatment.
Having shown that suitable GlyT1 inhibitor is disclosed chemical compound among the WO05/014563, for example, is formula I chemical compound:
Figure BDA00002825167200031
Wherein
Ar comprises one, substituted 6 yuan of heteroaryl groups of two or three nitrogen-atoms, and wherein said heteroaryl groups can be selected from by halogen, (C by one or more 1-C 6)-alkyl or the (C that is replaced by halogen 1-C 6The substituent group of the group that)-alkyl forms replaces;
R 1Hydrogen or (C 1-C 6)-alkyl;
R 2Replaced (C by halogen 1-C 6)-alkyl,
R 3, R 4And R 6Hydrogen, halogen, (C independently of one another 1-C 6)-alkyl or (C 1-C 6)-alkoxyl;
R 5SO 2R 10
R 10The optional (C that is replaced by halogen 1-C 6)-alkyl,
Or its medicinal acid addition salt, with and enantiomeric form.
Term " comprises one, 6 yuan of heteroaryls of the replacement of two or three nitrogen-atoms " expression monovalent aromatic carbocylic radical, for example, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl or 1,3,5-triazines base.
Term " halogen " expression chlorine, iodine, fluorine and bromine.For example, the term " (C that is replaced by halogen 1-C 6)-alkyl " expression following radicals: CF 3, CHF 2, CH 2F, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH 2CH 2CF 3, CH 2CH 2CH 2CF 3, CH 2CH 2Cl, CH 2CF 2CF 3, CH 2CF 2CHF 2, CF 2CHFCF 3, C (CH 3) 2CF 3, CH (CH 3) CF 3Or CH (CH 2F) CH 2F.
Term " medicinal acid addition salt " comprises and mineral acid and organic acid salt, described mineral acid and organic acid example hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, Fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-methyl benzenesulfonic acid etc.
In more detail, the objective of the invention is a kind of drug regimen that comprises atypical antipsychotic agents and GlyT1 inhibitor, described atypical antipsychotic agents is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone, and described GlyT1 inhibitor is selected from:
Raceme-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
Raceme-[4-(5-bromo-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(6-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((S or R)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((R or S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone, or
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1,1-dimethyl-ethyoxyl)-phenyl]-ketone.
More specifically; the present invention includes the atypical antipsychotic agents and GlyT1 inhibitor [4-(the 3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2 that are selected from the group that is formed by risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone; 2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-drug regimen of ketone.
The said medicine combination comprises the GlyT1 inhibitor of atypical antipsychotic agents and formula I, and described drug regimen is used for the treatment of the schizoid positive and negative symptoms.
Another object of the present invention is the application that drug regimen is used for the treatment of the schizoid positive and negative symptoms, and described drug regimen comprises the atypical antipsychotic agents that is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone and is selected from following GlyT1 inhibitor:
Raceme-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
Raceme-[4-(5-bromo-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(6-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((S or R)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((R or S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone, or
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1,1-dimethyl-ethyoxyl)-phenyl]-ketone.
In more detail; another object of the present invention is to comprise atypical antipsychotic agents and GlyT1 inhibitor [4-(the 3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2 that is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone; 2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-drug regimen of ketone is used for the treatment of the application of the schizoid positive and negative symptoms.
Another object of the present invention is the method that is used for the treatment of the schizoid positive and negative symptoms, described method comprises: to the combination that the people of the described treatment of needs uses atypical antipsychotic agents and the GlyT1 inhibitor of effective dose, the chemical compound that described GlyT1 inhibitor is formula I and medicinal acid addition salt thereof with and enantiomeric form.
Another embodiment is the method that is used for the treatment of the schizoid positive and negative symptoms, and described method comprises that the people to the described treatment of needs uses the atypical antipsychotic agents and the combination that is selected from following GlyT1 inhibitor of effective dose:
Raceme-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
Raceme-[4-(5-bromo-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(6-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((S or R)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((R or S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone, or
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1,1-dimethyl-ethyoxyl)-phenyl]-ketone.
More specifically; one embodiment of the invention are the methods that are used for the treatment of the schizoid positive and negative symptoms; described method comprises that the people to the described treatment of needs uses the atypical antipsychotic agents that is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone of effective dose and is selected from [4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2; 2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-combination of the GlyT1 inhibitor of ketone.
One embodiment of the invention are chemical compound 4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yls]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone (RG1678).
Figure BDA00002825167200061
Preferred combination comprises RG1678 and risperidone or olanzapine.
The RG1678 selectivity suppresses GLYT1, and GLYT1 is the transport protein [2.7,2.8] of the extracellular Glycine Levels of a kind of known control NMDA-R adjacent place brain.The increase of glycine causes the just adjusting to the NMDA-R synaptic activity, think its in schizophrenic's central nervous system be defective and/or function not good enough [2.8,2.9,2.10].Advantage with respect to existing psychosis therapy comprises the potentiality of improving negative symptoms and cognitive defect, the toleration characteristic (profile) that therefore this can cause better society and functional outcome and improvement does not have the susceptibility (1iabilities) of D2/5-HT2A kind fully.
Nmda receptor hypofunction hypothesis and GlyT1 suppress concept
In in the past 18 years by the research in normal individual and animal and by genetic analysis with suffer from the evidence that schizoid patient has been developed continuous increment, emphasize to relate in the schizoid pathophysiology NMDA-R hypofunction [2.4,2.10,2.11].Therefore, the therapeutic intervention of expectation take increase nmda receptor function as purpose has significant benefit [2.4,2.5,2.9,2.10] to schizophrenic's Mental Health.
Because glycine is the proprietary co-agonists [2.10] of NMDA-R complex, so the strategy of the neurotransmission of a kind of NMDA-R of enhancing mediation is the outer level of born of the same parents that improves glycine in the local microenvironment of Synaptic NMDA by suppressing glycine transporter 1 (GLYT1), described glycine transporter 1 (GLYT1) is sodium chloride dependency glycine transporter unique in the forebrain, itself and NMDA-R coexpression in forebrain, and be responsible for removing glycine [2.9,2.10] from synaptic space.Be reported as this method before some are clinical support is provided, proof also provides support [2.9,2.12,2.13] by the discovery that GLYT1 suppresses the transmission of adjusting dopaminergic nerve recently.
Glycine, D-Ser and sarcosine are as the clinical trial of adding therapeutic agent (add-on)
Other support about this method in treatment schizophrenia and psychosis comes from clinical research, wherein glycine and D-Ser (co-agonists in the glycine site of NMDA-R) and sarcosine (the weak GLYT1 inhibitor of prototype) improve the positive, feminine gender and awareness symptom [2.14 among the schizophrenic when adding in the conventional therapy, 2.15,2.16,2.17,2.18].
A kind of behavior determination for Rapid identification activity in vivo chemical compound (people such as D.Alberati, 2010 have been developed; Pharmacol Biochem, Behav (pharmacology, biochemistry and behavior) has received and has waited to announce).This method based in mice because by using L-687,414 ((3R, 4R)-3-amino-1-hydroxy-4-methyl pyrrolidin-2-one (a kind of partial agonist of the glycine site at the nmda receptor complex)) blocking-up nmda receptors and bring out fast moving behavior (hyperlocomotion).Show that glycine and GlyT1 inhibitor most likely block by L-687 by synapse glycine (using or GlyT1 suppresses to bring out by direct glycine) the dose dependent ground that raises; the 414 fast moving behaviors of bringing out; described synapse glycine raises can replace again the L-687 of nmda receptor binding site; 414, and therefore make the behavior change normalization of being brought out by the nmda receptor blocking-up.In addition, although observe psychoactive drug such as antidepressants benzodiazepine
Figure BDA00002825167200081
Class or analgesic can not prevent by L-687, the 414 fast moving behaviors of bringing out, but psychosis (haloperidol (haloperidol), olanzapine, risperidone and Aripiprazole) all effectively prevents this behavior effect in the dose dependent mode.Therefore, this novel behavior determination soundly (robustly) and detect reliably the activity in vivo of GlyT1 inhibitor and psychosis.
Improve the clinical research of the effect of the positive, feminine gender and awareness symptom among the schizophrenic when proving that glycine, D-Ser (co-agonists on the nmda receptor glycine site) and sarcosine (a kind of weak GLYT1 inhibitor) are in adding conventional therapy to, using L-687, the effect of research RG1678 and psychosis combination in 414 mices of attacking.
Materials and methods
Medicine
RG1678; [4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2; 2; 2 three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone (WO05/014563) and L-687; 414; ((3R; 4R)-3-amino-1-hydroxy-4-methyl pyrrolidin-2-one (Tetrahedron Letters (tetrahedron communication); 49 volumes; 42 phases; 2008,6079-6080) synthetic according to known method by the medical chemistry section of Huffman La Luoqi company (F.Hoffmann-La Roche) with olanzapine, risperidone is available from Sigma.All medicines all are dissolved in H 2In the O/0.3% Tween 80 and with the volume oral administration of 10ml/kg body weight.
Animal
Will be by French Iffa Credo, the male NMRI mice (20-30g) of Lyon supply was raised in cages in vivarium with temperature (20-22 ℃) and 12 hours bright/dark cycles (turning on light at 6:00a.m) of control.Allow the random contacting foodstuff of animal and water.Used experimental procedure is subject to Basel city animal protection committee (City of Basel Cantonal Animal Protection Committee) based on observing checking and approving in advance of federal and regional rules in this research.Carry out in the time course of behavioral experiment between 8:00a.m. and 2:00p.m.
The reverse of the fast moving behavior that L-687 in the mice, 414-bring out
Utilize computerized digital scan 16 animal activity monitoring systems (Digiscan 16 Animal Activity Monitoring System) (Omnitech Electronics, Columbus, Ohio) to quantize motor activity.Data are simultaneously available from eight digital scanning activity chambers that place between the sound insulation house with 12 hours bright/dark cycles.Experiment is carried out the photophase between 06:30a.m. and 5:00p.m.Each movement monitoring chamber is by plexiglas box (Plexiglas the box) (41x41x28cm that is surrounded with subtle horizontal and vertical infrared sensor light beam; W x L x H) forms, in the bottom of box sawdust bed is arranged.By the plexiglas cross chamber is separated, every mice provides the space of 20x20cm.Every box is monitored two animals simultaneously.The chamber is connected with digital scan analyser (Digiscan Analyzer), and described digital scan analyser is connected with computer, continues to collect the light beam status information.By light beam is counted come operant activity detector to discrete state or by discrete state to the change frequency of continuous state by continuous state.The photocell beam broken of per five minutes recording individual animals in the experimental session time-continuing process.The various dose that mice is at first used with p.o. or fixedly the RG1678 of low dosage process, and after 30 minutes, the various dose of using with p.o. or fixedly the psychosis of low dosage process.Psychosis was processed rear 15 minutes, and mice is accepted 50mg/kg L-687,414 s.c. injection.Then mice is transferred to 15 minutes the laundering period that recording room allows freely to probe into new environment by its cage of raising in cages.Then 60 minutes the time interval in the recording level activity.For the independent of given dose or with the RG1678 of psychosis combination, the horizontal anomalous movement value (y1) of every treated animal is expressed as L-687, the % of the fast moving behavior that 414-brings out, and calculate according to equation (((y1-excipient (vehicle) horizontal anomalous movement)/(L-687,414 horizontal anomalous movements-excipient horizontal anomalous movement)) x100).Test for dose dependent, GlyT1 inhibitor or psychosis for given dose, the horizontal anomalous movement value (y1) of every treated animal is expressed as L-687, the percent of the fast moving behavior that 414-brings out and calculate according to equation (((y1-excipient horizontal anomalous movement)/(L-687,414 horizontal anomalous movements-excipient horizontal anomalous movement)) x100).By using based on the computer curve fitting program of Excel the dose-response data are carried out linear regression analysis, calculate ID 50Value, described ID 50Value is defined as every kind of chemical compound and produces L-687,50% dosage that suppresses of the fast moving behavior that 414-brings out.
The result
In all experiments, use the L-687 of 50mg/kg dosage, 414, reason is before to find that comparing it with the animal of excipient-processing causes high and reliably behavior activation in mice.
RG1678, risperidone and olanzapine equal dose dependent in mice reverses L-687, the 414 fast moving behaviors of bringing out.
Fig. 1. Be added into the low dosage RG1678 of risperidone to L-687, the fast moving behavior that 414-brings out Effect.
Male NMRI mice is processed with RG1678 0.6mg/kg p.o., and after 30 ', the risperidone p.o. in 0.003 to 0.3mg/kg scope processes with dosage.After 15 ', give 50mg/kgL-687,414 subcutaneous injection.Control animal is only accepted excipient or accepts excipient and L-687,414.Begin to record motor activity after 15 minutes and continue 1 hour.Data are based on the average of every group of 8 animals.Ash solid line: independent risperidone; Black solid line: risperidone adds RG1678 0.6mg/kg; Black dotted line: 19% of the fast moving behavior of bringing out based on independent RG1678 reverses the effect of the risperidone of prediction and RG1678 0.6mg/kg.The ED of independent risperidone 500.023mg/kg.
The result
When adding the RG1678 (0.6mg/kg) of low dosage to risperidone (dose-response curve), the effect of this psychosis is increased to than the higher level (Fig. 1) of effect based on independent risperidone and independent RG1678 prediction.
Fig. 2: Be added into the low dosage risperidone of RG1678 to L-687, the fast moving behavior that 414-brings out Effect
Male NMRI mice is processed at 0.1 to 1mg/kg RG1678p.o. with dosage, after 30 ', process with risperidone 0.005mg/kg p.o..After 15 ', give 50mg/kg L-687,414 subcutaneous injections.Control animal is only accepted excipient or accepts excipient and L-687,414.Begin to record motor activity after 15 minutes and continue 1 hour.Data are based on the average of every group of 8 animals.Ash solid line: independent RG1678; Black solid line: RG1678 adds risperidone; Black dotted line: 15% of the fast moving behavior of bringing out based on independent risperidone reverses the effect of the RG1678 of prediction and risperidone 0.005mg/kg.The ED of independent RG1678 500.76mg/kg (Fig. 2).
The result
When adding the risperidone (0.005mg/kg) of low dosage to RG1678, observe the effect identical with Fig. 1 (dose-response).
Fig. 3 . be added into the low dosage RG1678 of olanzapine to L-687, the fast moving behavior that 414-brings out Effect.
Male NMRI mice is processed with RG1678 0.6mg/kg p.o., and after 30 ', the olanzapine p.o. in 0.003 to 0.3mg/kg scope processes with dosage.After 15 ', give 50mg/kgL-687,414 subcutaneous injections.Control animal is only accepted excipient or accepts excipient and L-687,414.Begin to record motor activity after 15 minutes and continue 1 hour.Data are based on the average of every group of 8 animals.Ash solid line: independent olanzapine; Black solid line: olanzapine adds RG1678 0.6mg/kg; Black dotted line: 21% of the fast moving behavior of bringing out based on independent RG1678 reverses the effect of the olanzapine of prediction and RG1678 0.6mg/kg.The ED of independent olanzapine 500.06mg/kg.
The result
Observe similar effect (dose-response curve) when adding the RG1678 (0.6mg/kg) of low dosage to olanzapine, wherein the effect of this psychosis is increased to equally than the higher level (Fig. 3) of effect based on independent olanzapine and independent RG1678 prediction.
Fig. 4: Be added into the low dosage olanzapine of RG1678 to L-687, the fast moving behavior that 414-brings out Effect.
Male NMRI mice is processed with the RG1678p.o. of dosage in 0.1 to 3mg/kg scope, after 30 ', process with olanzapine 0.05mg/kg p.o..After 15 ', give 50mg/kg L-687,414 subcutaneous injections.Control animal is only accepted excipient or accepts excipient and L-687,414.Begin to record motor activity after 15 minutes and continue 1 hour.Data are based on the average of every group of 8 animals.Ash solid line: independent RG1678; Black solid line: RG1678 adds olanzapine; Black dotted line: 34% of the fast moving behavior of bringing out based on independent olanzapine reverses the effect of the RG1678 of prediction and olanzapine 0.05mg/kg.The ED of independent RG1678 500.83mg/kg.
The result
When adding the olanzapine (0.05mg/kg) of low dosage to RG1678 (dose-response), can detect the RG1678 effect of obvious raising.Yet, in this combination, the effect of observing with based on the effect of the effect prediction of independent olanzapine and independent RG1678 near (Fig. 4).
In sum, following viewpoint is supported in these behavioral pharmacology researchs really: improve their effect with the low dosage RG1678 of psychosis combination.If the effect of more independent active component, then the effect of the combination of GlyT1 inhibitor and atypical antipsychotic agents is enhanced.
Atypical antipsychotic agents, olanzapine for example, with formula I chemical compound, and pharmaceutical salts can be used as medicine, for example, uses with the form of pharmaceutical preparation.Pharmaceutical preparation can be taken orally, for example, and with the form administration of tablet, coated tablet, lozenge (drag é es), hard and Perle, solution, Emulsion or suspensoid.Yet administration can also realize that by rectum for example, with suppository form, perhaps parenteral administration for example, is used with the injection form.
Formula I chemical compound can be with medicinal inertia, inorganic or organic carrier processing, with production pharmaceutical preparation.Can use lactose, corn starch, cellulose or derivatives thereof, Talcum, stearic acid or its salt etc., for example, be used for the examples of such carriers of tablet, coated tablet, lozenge and hard gelatin capsule.For example, the carrier that is fit to for Perle is vegetable oil, wax, fat, semisolid and liquid polyol etc.Yet depending on the character of active substance does not need carrier usually in the situation of Perle.The carrier that is fit to for the production of solution and syrup is, for example, and water, polyhydric alcohol, glycerol, plant wet goods.The carrier that is fit to that is used for suppository is, for example, and natural oil or fixed oil, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical preparation can comprise antiseptic, solubilizing agent, stabilizing agent, wetting agent, emulsifying agent, sweetener, coloring agent, flavoring agent, be used for changing salt, buffer agent, screening agent or the antioxidant of osmotic pressure.They can also comprise valuable material in other the treatment.
Comprise atypical antipsychotic agents, for example the medicine of olanzapine and formula I compound or pharmaceutically acceptable salt thereof and treatment inert carrier also is purpose of the present invention, technique about its production equally also is, it comprises makes one or more formulas I chemical compound and described psychosis and/or medicinal acid addition salt, and, if necessary, valuable material on one or more other treatments is made the galenic form of medication with one or more treatment inert carriers.
Dosage can change in wide region, and certainly must regulate for individual need in each concrete situation.In the situation of oral administration, be used for the adult dosage can from every day about 0.01mg extremely about 1000mg psychosis and compound of Formula I or its corresponding amount pharmaceutical salts and change.Daily dose can be used as single dose administration or with the divided dose administration, and in addition, when finding that this is instructed to need (indicated), also can surpass the upper limit.Normally, main atypical antipsychotic agents is with the dosage range administration according to the local prescription information of checking and approving.
Tablet formulation (wet granulation)
The project composition The mg/ tablet
Make each step
1. combined events 1,2, and 3 and 4 and use the pure water granulating.
2. at 50 ℃ of dried particles.
3. with the grinding equipment of granule by being fit to.
4. adding project 5 and mixing three minutes; Push at the tablet machine that is fit to.
Capsule preparations
The project composition The mg/ capsule
Figure BDA00002825167200132
Preparation process
1. in suitable blender, project 1,2 and 3 was mixed 30 minutes.
2. adding project 4 and 5, and mixed 3 minutes.
3. be filled in the suitable capsule.
The Olanzapine Tablets agent formulation
The project composition The mg/ capsule
Figure BDA00002825167200142
Preparation process
1. combined events 1-5 and use the pure water granulating.
2. at 50 ℃ of dried particles.
3. with the grinding equipment of granule by being fit to.
4. adding project 6 and mixing three minutes; Push at the tablet machine that is fit to.
Combination preparation
The project composition The mg/ capsule
Figure BDA00002825167200151
Preparation process
1. combined events 1-6 and use the pure water granulating.
2. at 50 ℃ of dried particles.
3. granule is by suitable grinding equipment.
4. adding project 7 and 8 and mixed three minutes; Push at the tablet machine that is fit to.
List of references
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2.10.Millan MJ.N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents:novel insights and clinical perspectives (conduct of NMA receptor is used for the target of the antipsychotic agent of improvement: novel viewpoint and clinical prospect) .Psychopharmacology (psychopharmacology) .2005; 179:30-53.
2.11.Harrison the people .Schizophrenia genes such as P, gene expression and neuropathology:on the matter of their convergence (schizophrenia gene, gene expression and neuro pathology: about its convergence) .Mol Psychiatry (molecule psychiatry) .2005; 10:40-68.
2.12.Lechner SM.Glutamate-based therapeutic approaches:inhibitors of glycine transport is (based on the treatment approach of glutamine: the inhibitor of glycine transporter) .Curr Op Pharmacol. (modern pharmacology viewpoint) 2006; 6:1-7.
2.13.Javitt the people .Modulation of striatal dopamine release by glycine transport inhibitors such as DC (regulation and control that glycine transporter inhibitors discharges striatal dopamine) .Neuropsychopharmacology (neuropsychopathy pharmacology) .2005; 30:649-656.
2.14.Heresco-Levy people .high-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia (the high dose glycine that is added into olanzapine and risperidone is used for the treatment of schizophrenia) .Biol Psychiatry (biology and the psychiatry) .2004 such as U; 15:165-171.
2.15.Tsai people .D-serine added to antipsychotics for the treatment of schizophrenia (D-Ser that is added into psychosis is used for the treatment of schizophrenia) .Biol Psychiatry (biology and the psychiatry) .1998 such as G; 44:1081-1089.
2.16.Heresco-levy the people .D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia such as U (effect that is used for the treatment of refractory schizophrenia as the D-Ser of the interpolation pharmacological treatment of risperidone and olanzapine) .Biol Psychiatry (biology and psychiatry) .2005; 15:577-585.
2.17.Tsai the people .Glycine transporter I inhibitors such as G, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia (be added into the glycine transporter I inhibitor of psychosis, sarcosine (sarcosine) is used for the treatment of schizophrenia) .Biol Psychiatry (biology and psychiatry) .2004; 55:452-456.
2.18.Lane the people .Sarcosine and D-serine add-on treatment for acute exacerbation of schizophrenia:a randomized such as HY, double-blind, placebocontrolled study (sarcosine and the D-Ser that are used for the schizophrenia acute exacerbation add treatment: at random, the research of double blinding, placebo) .Arch Gen Psychiatry.2005; 62:1196-1204.

Claims (14)

1. drug regimen, described drug regimen comprises: atypical antipsychotic agents and GlyT1 receptor antagonist, described GlyT1 receptor antagonist are the chemical compound of formula I,
Figure FDA00002825167100011
Wherein
Ar comprises one, substituted 6 yuan of heteroaryl groups of two or three nitrogen-atoms, and wherein said heteroaryl groups can be replaced by one or more substituent groups that are selected from by the following group that forms: halogen, (C 1-C 6)-alkyl or the (C that is replaced by halogen 1-C 6)-alkyl;
R 1Hydrogen or (C 1-C 6)-alkyl;
R 2Replaced (C by halogen 1-C 6)-alkyl,
R 3, R 4And R 6Hydrogen, halogen, (C independently of one another 1-C 6)-alkyl or (C 1-C 6)-alkoxyl;
R 5SO 2R 10
R 10The optional (C that is replaced by halogen 1-C 6)-alkyl,
And medicinal acid addition salt, with and enantiomeric form.
2. drug regimen according to claim 2, described drug regimen comprises the atypical antipsychotic agents that is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone and is selected from following GlyT1 receptor antagonist:
Raceme-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
Raceme-[4-(5-bromo-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(6-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((S or R)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((R or S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone, or
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1,1-dimethyl-ethyoxyl)-phenyl]-ketone.
3. drug regimen according to claim 2; described drug regimen comprises: the atypical antipsychotic agents and GlyT1 receptor antagonist [4-(the 3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2 that are selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone; 2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone.
4. drug regimen, described drug regimen comprises: be selected from atypical antipsychotic agents and the GlyT1 receptor antagonist of the group that is comprised of olanzapine or risperidone, described GlyT1 receptor antagonist is
And medicinal acid addition salt, with and enantiomeric form.
5. drug regimen according to claim 1, described drug regimen comprises atypical antipsychotic agents and GlyT1 receptor antagonist, and is used for the treatment of the positive and negative symptoms in the schizophrenia.
6. drug regimen is used for the treatment of the positive in the schizophrenia and the application of negative symptoms, and described drug regimen comprises atypical antipsychotic agents and GlyT1 receptor antagonist, and described GlyT1 receptor antagonist is the chemical compound of formula I:
Figure FDA00002825167100031
Wherein
Ar comprises one, substituted 6 yuan of heteroaryl groups of two or three nitrogen-atoms, and wherein said heteroaryl groups can be replaced by one or more substituent groups that are selected from by the following group that forms: halogen, (C 1-C 6)-alkyl or the (C that is replaced by halogen 1-C 6)-alkyl;
R 1Hydrogen or (C 1-C 6)-alkyl;
R 2Replaced (C by halogen 1-C 6)-alkyl,
R 3, R 4And R 6Hydrogen, halogen, (C independently of one another 1-C 6)-alkyl or (C 1-C 6)-alkoxyl;
R 5SO 2R 10
R 10The optional (C that is replaced by halogen 1-C 6)-alkyl,
And medicinal acid addition salt, with and enantiomeric form.
7. drug regimen according to claim 6 is used for the treatment of the positive in the schizophrenia and the application of negative symptoms, and described drug regimen comprises the atypical antipsychotic agents that is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone and is selected from following GlyT1 receptor antagonist:
Raceme-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
Raceme-[4-(5-bromo-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(6-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((S or R)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((R or S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone, or
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1,1-dimethyl-ethyoxyl)-phenyl]-ketone.
8. drug regimen according to claim 7 is used for the treatment of the positive in the schizophrenia and the application of negative symptoms; described drug regimen comprises: the atypical antipsychotic agents and GlyT1 receptor antagonist [4-(the 3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2 that are selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone; 2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone.
9. the application of drug regimen according to claim 8, described drug regimen comprises: be selected from atypical antipsychotic agents and the GlyT1 receptor antagonist of the group that is comprised of olanzapine or risperidone, described GlyT1 receptor antagonist is
Figure FDA00002825167100041
And medicinal acid addition salt, with and enantiomeric form.
10. one kind is used for the treatment of the positive in the schizophrenia and the method for negative symptoms, described method comprises: the combination of using atypical antipsychotic agents and the GlyT1 receptor antagonist of effective dose for the people of the described treatment of needs, the chemical compound that described GlyT1 receptor antagonist is formula I and medicinal acid addition salt thereof, with and enantiomeric form
Figure FDA00002825167100051
Wherein
Ar comprises one, substituted 6 yuan of heteroaryl groups of two or three nitrogen-atoms, and wherein said heteroaryl groups can be replaced by one or more substituent groups that are selected from by the following group that forms: halogen, (C 1-C 6)-alkyl or the (C that is replaced by halogen 1-C 6)-alkyl;
R 1Hydrogen or (C 1-C 6)-alkyl;
R 2Replaced (C by halogen 1-C 6)-alkyl,
R 3, R 4And R 6Hydrogen, halogen, (C independently of one another 1-C 6)-alkyl or (C 1-C 6)-alkoxyl;
R 5SO 2R 10
R 10The optional (C that is replaced by halogen 1-C 6)-alkyl.
11. the positive in the schizophrenia and the method for negative symptoms of being used for the treatment of according to claim 10, described method comprises: use the atypical antipsychotic agents of effective dose for the people of the described treatment of needs and be selected from the combination of following GlyT1 receptor antagonist:
Raceme-[4-(3-chloro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
Raceme-[4-(5-bromo-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone,
Raceme-[5-mesyl-2-(2,2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(6-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((S or R)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[5-mesyl-2-((R or S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-ketone,
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-((S)-2,2,2-three fluoro-1-methyl-ethyoxyls)-phenyl]-ketone, or
[4-(3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2,2,2-, three fluoro-1,1-dimethyl-ethyoxyl)-phenyl]-ketone,
Described combination is used for the treatment of the negative symptoms in the schizophrenia.
12. the positive in the schizophrenia and the method for negative symptoms of being used for the treatment of according to claim 11; described method comprises: the atypical antipsychotic agents that is selected from the group that is comprised of risperidone, Paliperidone, olanzapine, Aripiprazole, Quetiapine or Ziprasidone and selected GlyT1 receptor antagonist [4-(the 3-fluoro-5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-[5-mesyl-2-(2 that use effective dose to the people of the described treatment of needs; 2,2-, three fluoro-1-methyl-ethyoxyls)-phenyl]-combination of ketone.
13. the positive in the schizophrenia and the method for negative symptoms of being used for the treatment of according to claim 12 comprises the atypical antipsychotic agents and the GlyT1 receptor antagonist that are selected from the group that is comprised of olanzapine or risperidone, described GlyT1 receptor antagonist is
Figure FDA00002825167100061
Or its medicinal acid addition salt, with and enantiomeric form.
14. aforesaid invention.
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